Microdroplets, originally called monolayer vesicles, were previously used to study the properties of the phospholipid surface as a model for the true phospholipid vesicle which, in turn, was a model for the biological membrane. This approach is to be distinguished from liposomes (multilamellar-) and unilamellar phospholipid vesicles used to deliver water-soluble drugs to the interior of cells, both in vivo and in vitro. These liposomes are true vesicles and consist of a spherical lipid bilayer with an aqueous phase inside.
Microdroplets are known and consist of spheres of organic liquid phase drug approximately 500 Angstroms in diameter and range from 200 Angstroms up to at least one micron (10,000 Angstroms) in diameter and are covered with a monolayer of a suitable phospholipid.
The microdroplets of my invention can be used to deliver any water-insoluble/oil-soluble drug compound via injection. Most non-polar drugs now taken orally are contemplated and are within the scope of the invention. The organic liquid phase may be the drug itself, a general anesthetic medium, fluorocarbons, vegetable oil or mineral oil. The advantages of the microdroplets provided by my invention include a relatively slow release of the drug substance to the tissues and allow for a targeted delivery by intelligent choice of the site of injection with lowered metabolic degradation, first pass effects, and toxic side-effects in the liver and other organs.
Local anesthesia is conventionally accomplished by injection of water-soluble compounds into the site to be anesthetized. For efficacy the drugs need both hydrophobic properties, to bind to and cross cell membranes, and hydrophilic properties, to dissolve in water and diffuse to the site of action. The duration of anesthesia is limited by the fairly rapid process of absorption of the injected anesthetic into the blood. The currently-used example of a longacting local anesthetic is bupivacaine which gives anesthesia for a few hours in some applications. There is a considerable need for a local anesthetic of longer duration, preferably of significantly longer duration. Instances of the need for longer anesthetic duration include the control of post-operative pain, relief of chronic pain in cases of pinched nerves, back pain and other applications requiring long-term nerve conduction block and the like. Management of long-term pain is done by analgesics, such as aspirin and opiods, but these are often ineffective and sometimes give unwanted side-effects.
In contrast to local anesthesia is general anesthesia, which is accomplished by inhalation of anesthetic gases to produce unconsciousness. These include nitrous oxide, halothane, isoflurane, enflurane and methoxyflurane. The first-named example is a true gas; the others are volatile fluoro-chloro-hydrocarbons which exist in liquid form. Liquid general anesthetics are water-insoluble and immiscible. They are volatized into the air which the patient breathes, they gain access to the circulation through the lungs and cause unconsciousness by binding to the nerve membranes in the brain.
The novelty of one embodiment of my invention lies in the fact that it uses general anesthetics as local anesthetics. According to a current popular conception of physicians and biomedical scientists the use of inhalation anesthetics as local anesthetics is impossible. The textbooks and scientific papers deal with the local anesthetics and the general (often termed "volatile" and "inhalation" anesthetics) as separate classes of drug substances. According to contemporary thought this division is correct since the volatile anesthetics exist as oil-like liquids which are impossible to inject due to their low solubility in water--injection as such would be unthinkable. Injection of a liquid phase of any of the volatile anesthetics would result in membrane delipidation, cellular damage and eventual tissue necrosis. Dilution of such agents in saline is not feasible because of their water-insolubility. Yet it is this low water-solubility and high solubility in the membrane phase which makes these agents effective blockers of nerve conduction in the brain (and elsewhere, but with less physiological consequence).